1,5,7-Triazabicyclo[4.4.0]dec-5-ene Enhances Activity of Peroxide Intermediates in Phosphine-Free α-Hydroxylation of Ketones

Article abstract of DOI:10.1002/anie.202014478

The critical role of double hydrogen bonds was addressed for the aerobic α-hydroxylation of ketones catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), in the absence of either a metal catalyst or phosphine reductant. Experimental and theoretical investigations were performed to study the mechanism. In addition to initiating the reaction by proton abstraction, a more important role of TBD was revealed, that is, to enhance the oxidizing ability of peroxide intermediates, allowing DMSO to be used rather than commonly used phosphine reductants. Further characterizations with nuclear Overhauser effect spectroscopy (NOESY) confirmed the presence of double hydrogen bonds between TBD and the ketone, and kinetic studies suggested the attack of dioxygen on the TBD-enol adduct to be the rate-determining step. This work should encourage the application of TBD as a catalyst for oxidations.

Full text of DOI:10.1002/anie.202014478

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Accepted Article
Title: TBD-Enhanced Activity of Peroxide Intermediates in Phosphine-
Free α-Hydroxylation of Ketones
Authors: Yongtao Wang, Rui Lu, Jia Yao, and Haoran Li
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RESEARCH ARTICLE
1,5,7-Triazabicyclo[4.4.0]dec-5-ene Enhances Activity of Peroxide
Intermediates in Phosphine-Free -Hydroxylation of Ketones
Yongtao Wang, Rui Lu, Jia Yao, Haoran Li*
[*]
Dr. Y. Wang, R. Lu, Dr. J. Yao, Prof. Dr. H. Li
Department of Chemistry and ZJU-NHU United R&D Center
Zhejiang University
38 Zheda Road, Hangzhou, 310027, P. R. China
E-mail: lihr@zju.edu.cn
Prof. Dr. H. Li
State Key Laboratory of Chemical Engineering and College of Chemical and Biological Engineering
Zhejiang University
38 Zheda Road, Hangzhou, 310027, P. R. China
Supporting information for this article is given via a link at the end of the document.
Abstract: The critical role of double hydrogen bonds was addressed
for the aerobic -hydroxylation of ketones catalyzed by 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD), in absence of either metal
catalyst or phosphine reductant. Experimental and theoretical
investigations were carried out to study the mechanism. In addition to
initiating the reaction by proton abstraction, a more important role of
TBD was revealed to enhance the oxidizing ability of peroxide
intermediates, allowing DMSO an efficient substitute of commonly
used phosphine reductants. Further characterizations with the nuclear
Overhauser effect spectroscopy (NOESY) confirmed the double
hydrogen bonds between TBD and ketone, and kinetic studies
suggested the attack of dioxygen on the TBD-enol adduct to be the
rate-determining step. This work uncovered the enhancing role of
TBD on the oxidizing ability of peroxides, and should encourage the
application of TBD as a catalyst for oxidations.
phosphine reductant.[9] The use of stoichiometry base or
phosphine reductant is required in above mentioned methods,
thus a more green catalysis system is of interest to oxidize the -
C(sp3)-H bond in ketones.
Mechanistically (Figure 1), it is commonly accepted that the
hydroxylation is initiated by proton abstraction, and both
carbanion[7-8] and enol[9] have been proposed as the intermediate,
which then react with dioxygen to form peroxide intermediate.
Phosphine reductant was generally used for reducing the
peroxide intermediate,[7] otherwise this intermediate would form
the carboxylic acid byproduct via C−C cleavage.[6] However, when
studying the hydroxylation of ketones in DMSO, we found that
catalytic amount of TBD could lead to a high yield, and the loading
of Cu2O catalyst had no beneficial effect (Figure S1). The green
and efficient aerobic hydroxylation under the metal- and
phosphine-free condition encouraged us to investigate the
catalytic role of TBD.
Introduction
The selective C-H bond oxidation by dioxygen has been
pursued for a long time.[1] As an oxygenation product of the -
C(sp3)-H bond, the -hydroxy-carbonyl group commonly exists in
natural products and bioactive molecules,[2] and shows potential
usages as the photoinitiator and the privileged synthon.[3]
Although it is the most sustainable and green oxidant, dioxygen is
difficult to react directly with C-H bond.[4] The aerobic oxygenation
of -C(sp3)-H bond in ketones was mostly initiated by bases, with
excess phosphine reductants added for high selectivity. Ritter
group reported a highly efficient binuclear palladium catalyst for
aerobic -hydroxylation of carbonyl compounds,[5] and introduced
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as both ligand and
additive. Schoenebeck and coworkers achieved the aerobic
oxidation of ketones in DMSO using Cu2O catalyst along with
stoichiometry TBD,[6] and they uncovered the detailed C−C
cleavage mechanism as well as substrate-dependent selectivity.
Instead of transition-metal catalysts, Jiao group developed a
highly efficient method, in which Cs2CO3 was used as catalyst.[7]
Besides, 2 equiv P(OEt)3 was added to reduce the peroxide
intermediate. More recently, Gnanaprakasam et al. also
developed a transition-metal-free method,[8] avoiding the use of
phosphine reductant by introducing stoichiometry KOtBu. Besides,
Zhao and coworkers fulfilled the enantioselective -hydroxylation
using the phase-transfer catalysts with aqueous KOH as well as
Figure 1. Previously proposed mechanism for aerobic hydroxylation of carbonyl
compounds.
Though TBD has been introduced in the hydroxylation of
ketones, its role is still not clear. Ritter and coworkers found that
TBD was not solely a base,[5] because the replacement of TBD by
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 7-methyl-1,5,7-
triazabicyclo-[4.4.0]dec-5-ene (MTBD) led to poor performance.
Schoenebeck and co-workers suggested that the TBD worked as
both base and reductant,[6] thus they used stoichiometry TBD in
their system. Due to lack of detailed investigations, the
controversy still remains over the role of TBD. Besides, TBD has
been widely used as the catalyst in many reactions owing to its
special structure,[10] especially in addition reactions and ring-
1
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10.1002/anie.202014478
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opening polymerizations.[11] In these reactions, the double
hydrogen bonds were proposed for the TBD promoted proton
transfer.[12] Recently, Dale and coworkers reported the control of
regioselectivity for N-alkylation by TBD.[13] The tightly combined
TBD-triazole adduct through double hydrogen bonds was
determined with X-ray diffraction as well as the diffusion-ordered
1H NMR spectroscopy (DOSY).
Herein, we report the TBD-catalyzed aerobic -hydroxylation
of ketones in free of either metal catalysts or phosphine
reductants. DMSO as the solvent was revealed to reduce the
peroxide intermediates toward hydroxylated products. The role of
TBD and detailed mechanism were investigated by means of
control experiments, isotropic labeling experiments, kinetic
studies, 1H-NMR, the nuclear Overhauser effect spectroscopy
(NOESY), combined with computational calculations. As a result,
the dual catalytic role of TBD via doubly proton transfer process
was revealed, uncovering the TBD-enhanced activity of peroxide.
When processing the TBD participated aerobic hydroxylation
of 2-methyl-1-tetralone (1a) in DMSO, we found the use of metal
catalyst or phosphine reductant was not necessary (Figure S1).
Even the TBD loading could be as low as catalytic amounts.
Tsang et al. considered TBD both a base and the reductant for
the peroxide intermediate,[6] and they used 1.1 equiv TBD in place
of phosphine reductant in the Cu2O-Catalyzed hydroxylation.
During our study, to our delight, as the TBD loading was reduced
from 100 mol% to 20 mol% (Table 1, entries 1-5), comparable
yield of 2a was obtained (from 97% to 93%), despite the decrease
of reaction rate. It is reasonable that catalytic amounts of TBD can
initiate this reaction via proton abstraction, however, the
confusing issue is how the peroxide intermediate is reduced to 2a
in absence of phosphine reductant.
Firstly, we investigated the influencing factors. Several
solvents were utilized in place of DMSO to evaluate the solvent
effect (Table 1, entries 6-11), but none of them performed better.
The reactions in toluene, THF, butanol and 1,4-dioxane occurred
in much low conversion and yield for hydroxylation, while 2a was
in yield of only 11% in DMA and 14% in DMF. Considering
different types of bases as catalysts (Table 1, entries 12-14), we
found K2CO3 was not basic enough to initiate the reaction, while
the selectivity was too low with 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) (27%) and Cs2CO3 (20%), though they should be basic
enough. The byproduct of this reaction has been detected to be
carboxylic acid,[6] by which the basic catalyst could be passivated
during the reaction. Therefore, the low conversion with DBU and
Cs2CO3 should be caused by the low selectivity. Consequently,
using DMSO as the solvent and TBD as the catalyst is required
to gain high selectivity for hydroxylation, which should depend on
the competition between C−C cleavage and reduction of the
peroxide intermediate.
Results and Discussion
Reaction development and influencing factor examination
Table 1. Effects of different parameters on the oxidation of 1a using dioxygen[a]
.
Entry
Cat. (equiv)
Solvent
Time
[h]
Conv.
[%]
Yield
[%]
1
TBD (1.0)
TBD (0.8)
TBD (0.6)
TBD (0.4)
TBD (0.2)
TBD (0.2)
TBD (0.2)
TBD (0.2)
TBD (0.2)
TBD (0.2)
TBD (0.2)
K2CO3 (0.2)
DBU (0.2)
Cs2CO3 (0.2)
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
THF
2
100
100
100
100
100
8
97
96
94
92
93
3
2
2
3
5
4
5
5
12
12
12
12
12
12
12
12
12
12
6
7
5
1
8
n-Butanol
1,4-dioxane
DMA
11
2
9
8
1
10
11
12
13
14
24
11
14
0
DMF
50
DMSO
DMSO
DMSO
N.R.
11
3
10
2
[a] Conditions: substrate (0.5 mmol), catalyst (0.1-0.5 mmol), solvent (2 mL); the
reaction was performed at room temperature with 1 atm O2. The conversion and
yield were determined using gas chromatography (GC) with biphenyl as the
internal standard. [b] The value in parentheses was the catalyst loading in
equivalent.
Scheme 1. Scope of TBD-catalyzed hydroxylation. The yield was obtained for
isolated product under standard conditions (Table 1, entry 5). [a] 50 mol% TBD
was used. [b] The reactions were detected using 1H NMR with 1,3,5-
trimethyoxybenzene as internal standard.
2
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Under the optimized condition, the reaction scope was
examined (Scheme 1). The secondary -carbon at
cyclohexanone (1n) was found inactive, while 1o and 1p with
tertiary -carbon could yield hydroxylated products, 2o and 2p.
The ester 1m did not react in this condition, but substitutions at -
carbon with carbonyl or phenyl could activate esters, leading to
acceptable yields (2h-2l). Therefore, the reactivity of ketones
should be affected by the acidity of -proton, then activating
groups like phenyl and carbonyl at -site would benefit this
reaction. Moreover, cycloketones were found to generate more
hydroxylated products than the chain ketones (2b vs. 2d). Though
the phenyl group at 1e made it reactive, only 45% 2e was
obtained even in use of 50 mol% TBD, thus, a low selectivity could
be supposed for 2e. We will return to explain these different
reactivities and selectivities later, after mechanism investigations.
Scheme 2. (a) Reaction of 1a with 18O-labeled dioxygen. (b) Reaction of 1a in
presence of 2.0 equiv TEMPO as the radical inhibitor.
Considering the ionic mechanism has been proposed for the
hydroxylation of ketones,[1a] we also suggested the ionic
mechanism for the hydroxylation of 1a in this work, where DMSO
played the role as reductant. The 2.0 equiv TEMPO was added at
the beginning of the reaction to inhibit possible radical routes,
however, no apparent decrease of the yield was observed after
full conversion (83% vs. 93%, Scheme 2b). Because the reaction
not inhibited by TEMPO was found inhibited by 3,5-di-tert-4-
butylhydroxytoluene (BHT),[15] and the acidic phenol will inactivate
the basic TBD in our conditions, we could only propose this ionic
mechanism, but could not absolutely confirm.
Identifying the reductant for peroxide intermediates
It has been proved that the peroxide intermediate was formed
14]
during the aerobic hydroxylation of carbonyl compounds.[8,
Generally, this intermediate is reduced efficiently by phosphine
9]
reductants such as P(OEt)3 and PPh3.[7,
Considering no
phosphine reductant used but comparable yield obtained in this
work, next, we focus on determining whether there is another
species playing the role to reduce peroxide intermediates.
By monitoring the reaction of 1a with gas chromatography
(GC), we found that dimethyl sulfone (DMSO2) arose along with
the production of 2a (Figure S3-4). The generation of DMSO2
allowed us to suppose DMSO as the reductant to convert the
peroxide intermediate to 2a. In order to test whether DMSO
participated in the hydroxylation, we related the consumed
dioxygen (detected using a communicating vessel, Figure S2) as
well as the produced DMSO2 with the reacted substrate. As
shown in Figure 2, equivalent dioxygen was consumed along with
the reaction of 1a (Figure 2, black, y = 1.04x - 0.012), and
equivalently generated DMSO2 (Figure 2, red, y = 0.096x – 0.105).
These correlations verified the participation of DMSO in the
hydroxylation of 1a as the reductant. The other evidence was
attained from the 18O-labelling experiments (Scheme 2a). When
18O-labeled dioxygen was used to oxidize 1a, both the
hydroxylated product 2a and DMSO2 were found to be
incorporated by one 18O atom, characterized by GC-MS (Figure
S5). On the basis of above results, both quantitative studies and
18O-labelling experiments supported our previous conjecture that
DMSO was the oxygen acceptor of the peroxide intermediate.
TBD-enhanced activity of peroxide intermediates
Though DMSO has been revealed as the reductant, the
reaction catalyzed by Cs2CO3 in place of TBD could not occur in
comparable selectivity (Table 1, entry 14). Using phosphine
reductant, however, Liang and Jiao have proved Cs2CO3 an
efficient catalyst for the hydroxylation of ketones.[7] Thus, the
alkalinity of Cs2CO3 alone was strong enough to initiate the
reaction, and the other function of TBD except alkalinity should be
required for the reduction of peroxide by DMSO. As a support, the
addition of Cs2CO3 into TBD/DMSO system apparently
accelerated the reaction (Table 2, entries 1-2), improving the
conversion from 69% to 100% at 2 h, with similar selectivity (90%
vs. 91%).
In light of the unique efficiency of TBD for the high selectivity,
we evaluated the effect of structure characteristic on its catalytic
role. The methylation of the amino group in TBD results in another
guanidine, 7-methyl-1,5,7-triazabicyclo-[4.4.0]dec-5-ene (MTBD),
which has the similar pKBH+ value (25.4 in MeCN) as that of TBD
(26.0 in MeCN).[16] Taking MTBD in place of TBD, however, the
reaction gave much lower conversion (12%), and did not afford
hydroxylated product in acceptable selectivity, not even with the
addition of Cs2CO3 (Table 2, entries 3-4). Thus, the amino group
is crucial for the catalytic role of TBD.
Bicyclic guanidines, including TBD, MTBD and DBU, have
11c, 17]
been commonly used as the strong organic base,[10-11,
where TBD showed much higher activity for the reactions
involving proton transfer, like Michael reactions,[11b] or ring-
opening polymerization of lactones.[11e, 18] The high performance
of TBD was suggested to be caused by its unique structural
characteristic,[10, 12] which allowed the double proton transfer via
forming double hydrogen bonds. Moreover, during the N-
alkylation of triazoles, the double hydrogen bonds between TBD
and triazole lead to the high regioselectivity.[13] Therefore, in our
reactions, we surmised that the double proton transfer was
involved in the TBD-catalyzed reduction of peroxide intermediates.
Figure 2. The relationship between the reacted substrate and the consumed
dioxygen (■), produced DMSO2 (●) or formed product (∆).
3
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10.1002/anie.202014478
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positively charged sulfur atom at DMSO. As a result, the TBD-
enhanced activity of peroxide allowed its reaction with DMSO.
Table 2. Control experiments[a]
.
Though the double proton transfer has been reported in TBD-
19]
catalyzed reactions,[12,
to the best of our knowledge, its
application on enhancing the reactivity of peroxide has not been
uncovered yet.
Afterward, we used two commercially available peroxides,
cumene hydroperoxide (CHP) and tert-butyl-hydroperoxide
(TBHP), to react with d6-DMSO, in the hope of verifying the
Entry
Cat.
Additive
none
Time
[h]
Conv.
[%]
Sele.
[%]
1
2
3
4
TBD
2
69
91
90
33
33
1
catalytic activity of TBD on the reduction of peroxides. With H-
NMR spectra, the yield was determined based on the peak area
of methyl group (Table 3, also see Figure S6). Stirring CHP in d6-
DMSO for 48 h, little CHP was reduced, producing 2% 2-Ph-2-
propanol (entry 1). To our delight, when 20 mol% TBD was used,
CHP fully conversed to 2-Ph-2-propanol (entry 2). Meanwhile, the
generation of DMSO2 was confirmed by GC-MS (Figure S7).
Under the same condition, but with MTBD in place of TBD, only
19% 2-Ph-2-propanol was obtained. The higher efficiency of TBD
than MTBD was also observed for the reaction of TBHP (entries
4-5, Figure S8), where 39% and 4% tert-butanol was produced
under the catalysis of TBD and MTBD, respectively. Due to the
wide applications of CHP and TBHP as oxidants, the
enhancement of their oxidizing ability by TBD may help improving
their reactivity or broadening their applications.
TBD
Cs2CO3 (20 mol%)
none
2
100
12
MTBD
MTBD
12
2
Cs2CO3 (20 mol%)
15
[a] The conversion and selectivity were determined using GC with biphenyl as
the internal standard.
1H-NMR experiments supported the proposed mechanism for
the promoting effect of TBD on peroxide reduction. Figure 4
illustrates the change of 1H-NMR spectra during the TBD-
catalyzed reduction of CHP in d6-DMSO. The signals in dashed
box are 40-fold decreased, belonging to the methyl group at CHP
(star-labeled) or that at 2-Ph-2-propanol (spade-labeled). In
addition, when TBD was added into the solution of CHP in d6-
DMSO, the peak for exchangeable proton at CHP shifted upfield
from 11.0 toward 6.6 ppm, suggesting the proton exchange or the
existence of hydrogen bonds between TBD and CHP. Combining
with the results of theoretical study, we supposed that TBD
interacted with CHP through the double hydrogen bonds,
enhancing the oxidizing ability of CHP, then the doubly proton
transfer made the reaction between CHP and DMSO passable.
As CHP was reduced to 2-Ph-2-propanol, the peak of the
exchangeable proton continued shifting upfield toward 4.3 ppm.
Consequently, the catalytic role of TBD was confirmed for the
reduction of peroxides, where the doubly proton transfer process
was suggested.
Figure 3. (a) Gibbs free energy profile for reduction of the peroxide intermediate
by DMSO, with (blue) and without (red) TBD. (b) The electrostatic potential
(ESP) on the 0.01 au isodensity surface of the peroxide intermediate without
(left) and with (right) TBD linked (C: grey, H: white, N: blue, O: red).
We carried out DFT calculations to evaluate the influence of
double hydrogen bonds on the peroxide reduction, where the key
step is the formation of S-O bond. By searching the transition
state (Figure 3a, TS-3), we found the formation of S-O bond was
along with the breaking of O-O bond, accompanied by proton
transfer, generating 2a. In absence of TBD, this step was
forbidden, with activation free energy as high as 32.2 kcal/mol.
Driving by the double hydrogen bonds, the peroxide intermediate
thermodynamically tended to combine with TBD (G = -16.2
kcal/mol), and then its reaction with DMSO (through TS-6) was
19.4 kcal/mol favored, resulting in a passible activation free
energy, 12.8 kcal/mol. Moreover, the charge distribution at
peroxide might account for the catalytic activity of TBD. Figure 3b
illustrates the electrostatic potential (ESP) of the peroxide
intermediate without and with TBD linked. According to color
range, we can find that the negative potential at the peroxide
oxygen was apparently enhanced by TBD. With more negative
charge at oxygen, the peroxide was motivated to attack the
Table 3. Reduction of peroxides in d6-DMSO[a]
.
Entry
1
Sub.
CHP
Cat.
Time [h]
48
Yield [%]
2
none
2
3
4
5
CHP
CHP
TBD
MTBD
TBD
48
48
48
48
100
19
39
4
TBHP
TBHP
MTBD
[a] The yield was determined in use of 1H-NMR.
4
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attributed to the existence of double hydrogen bonds, for their
spatially close range. Moreover, the thermodynamic preference of
the double hydrogen bonds was also verified by DFT calculations,
discussed later.
Figure 4. 1H-NMR spectra for the reduction of CHP in DMSO. Signals in the
dashed box are 40-fold decreased, and the chemical shift was given in ppm.
Mechanistic studies on the aerobic C-H oxygenation
The above studies revealed mechanistic insights into the
reduction of peroxide intermediate, which determines the
selectivity for hydroxylation. Following, we focus on the reactivity
of ketones toward dioxygen. The triplet dioxygen is
thermodynamically unfavorable to react with the -C-H bond at
ketones.[4] Without metal catalyst to activate dioxygen, in this
reaction, carbanion should be formed via -proton abstraction
with the help of basic catalyst, then readily reacts with dioxygen.
Several groups have reported the excellent ability of TBD for
18-20]
proton abstracting,[11b-e,
and the doubly proton transfer
mechanism was also proposed. With much effort, we observed
the interaction between ketone and TBD in use of NMR, then
kinetic experiments and theoretical calculations were carried out
to investigate the rate-determining step.
To characterize the interaction between TBD and 1a, we
concerned the 1H NMR signal of amine group at TBD (Figure 5a).
In absence of ketones, the 0.25 M TBD in d6-DMSO showed a
broad peak at 4.83 ppm, belonging to the exchangeable proton of
its amine group. Adding 0.5 and 1.0 equiv 1a to this solution at N2
atmosphere, the chemical shift of this signal shifted from 4.83 to
5.07 and 5.29 ppm, respectively. According to the reported
relationship between chemical shift and hydrogen bond
strength,[21] such downfield peak shift ( = 0.46 ppm) should
suggest the formation of hydrogen bond between TBD and 1a.
Moreover, when two protons are spatially close, the dipolar
cross-relaxation can be detected by the two-dimensional nuclear
Overhauser effect spectroscopy (2D NOESY).[22] With this
method, hopefully, the combination of TBD and ketone might be
identified through the cross peak between protons. To avoid the
influence of signal interference (Figure S9), we took 1b in place
of 1a for NOESY analyses, and characterized the equivalently
mixed TBD with 1b in d6-DMSO under N2 atmosphere (Figure 5b).
According to the heteronuclear Overhauser effect spectroscopy
(HOESY, Figure S10), the signal belonging is signed at the side
1H NMR spectra, and the expanded peak is given for the
exchangeable proton at TBD, along with that in absence of 1b. As
expected, cross peaks were observed between the exchangeable
proton at TBD (Ha) and the -proton at 1a (Hc), confirming the
hydrogen-bonded 1a with TBD. To our delight, the Hc was also
found spatially correlated with the methylene proton at TBD (Hd).
The observation of Hc-Hd and Ha-Hd correlations could be
Figure 5. (a) 1H NMR spectra of the exchangeable proton at TBD in d6-DMSO
(0.25 M), with addition of 0, 0.5, and 1 equiv 1a. (b) The symmetrized H,H-
NOESY spectrum of the equivalently mixed 1b and TBD in d6-DMSO (0.25 M).
The enlarged signal of the exchangeable proton at TBD was given along with
that in absence of 1b (grey).
Figure 6. The relationship between kobs and the concentrations of TBD without
(■) or with (●) hydrogen deuterated, for determining the second-order rate
constants and kH/kD.
5
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Further kinetic experiments were conducted to explore the
rate-determining step. By monitoring the reaction with GC, we
found the concentration of 1a followed the exponential decay
(Figure S11), indicating a first-order kinetic for the reaction of 1a.
Besides, by detecting the observed rate constant (kobs) with
different amounts of TBD, we found the reaction also followed a
first-order kinetic for TBD (Figure 6, black). Fitting with the linear
function, a second order rate constant (k2) of 0.187 M-1 s-1 was
obtained. Such results indicate the equivalently participating of
ketone and TBD in the rate-determining step. In addition, when
the -proton at 1a and the exchangeable proton at TBD were
deuterated (Figure S12), the reaction rate was decelerated, with
k2 = 0.133 M-1 s-1 (Figure 3, red). Accordingly, the KIE was
calculated to be 1.41, much lower than the commonly observed
primary isotope effect, belonging to the secondary isotope
effect.[23] Therefore, the rate-determining step of this reaction
could not be the C-H bond breaking, then was proposed to be the
attack of dioxygen on the TBD-combined enol intermediate, with
O-H bond involved.
Figure 7. Gibbs free energy profile for hydroxylation of 1a catalyzed by TBD (blue) or MTBD (red). The free energies (with DMSO solvation) are given in kcal/mol.
(C: grey, H: white, N: blue, O: red). Distances are shown in angstrom.
As illustrated in Figure 7, DFT calculations were carried out
for the hydroxylation of 1a catalyzed by TBD (blue) and MTBD
(red). Benefitting from the double hydrogen bonds, the former was
apparently favorable in Gibbs free energy. The doubly proton-
transfer process (through TS-1) was 7.3 kcal/mol favored than
that of the one proton-transfer process (through TS-4), and
generated the TBD-enol adduct with double hydrogen bonds kept.
Being slightly endothermic (3.9 kcal/mol), the -proton transfer for
the substrate was reversible. Here the stabilization of enol by TBD
was quite important to the whole reaction, because it lead to a
much lower thermodynamic penalty from ketone to enol, which
has been found to be about 10 kcal/mol and was one of the key
kinetic obstacles for this type of transformation.[24] After another
endothermic process (1.4 kcal/mol), there formed an enol
intermediate with TBD combined at the O-H group. The attack of
triplet dioxygen on the enol intermediate should go through a spin
transition process. Thus, we performed a MECP (minimum
energy crossing point) calculation to find the singlet-triplet
crossing point, and obtained a structure with lower energy than
that of the triplet transition state. Thus, the Gibbs free energy
barrier was calculated to be 22.9 kcal/mol. As a result, the C-O
bond formation served as the rate-determining step. Accordingly,
it is reasonable that the first-order kinetic was found for both 1a
and TBD. The formation of C-O bond was accompanied by the O-
H bond breaking, leaving TBD-H+ to combine with the -OO- group,
forming the TBD-associated peroxide intermediate.
As to the MTBD catalyzed pathway, both substrate activating
and peroxide reduction were slowed down, especially, the
reduction of peroxide intermediate by DMSO turned to be the rate-
determining step and was impassable (32.2 kcal/mol). Therefore,
the carboxylic acid should be generated during the MTBD
catalyzed pathway, and would inactive the catalyst by the
neutralization reaction, leading to low conversion. Consequently,
the DFT studies reinforced a consistent mechanism with that
suggested by the experimental results.
Proposed catalytic cycle
According to the above discussed studies on the mechanism,
we proposed the catalytic cycle for the TBD catalyzed oxidation
of ketones (Figure 6). Firstly, TBD combines with ketone through
the double hydrogen bonds. Then the -proton was abstracted by
the imide group at TBD, accompanying with the proton
transferring from the amino group at TBD to the carbonyl oxygen.
The synergistic doubly proton-transfer process promoted the -
proton transferring, and generated a double hydrogen bonds
stabilized enol with TBD. After the breaking of the N-H group from
6
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10.1002/anie.202014478
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RESEARCH ARTICLE
-site sp2-carbon, the attack of dioxygen on the enol was the rate-
determining step, leading to the formation of peroxide
intermediate. Most importantly, TBD enhances the oxidizing
ability of peroxide intermediate via the double hydrogen bonds,
allowing its reaction with DMSO. The hydroxylated product was
generated after the reduction, while the DMSO was oxidized to
DMSO2. Moreover, suggested by Schoenebeck et al.,[6] the
unreduced peroxide would proceed the C-C cleavage to produce
carboxylic acid and ketone as the byproducts. In this mechanism,
TBD played the dual catalytic role in both substrate activation and
peroxide reduction, via the doubly proton-transfer process.
ketones via proton abstraction, where the double hydrogen bonds
between TBD and ketones were characterized with both 1D H
1
NMR and 2D NOESY. The role for proton abstraction depends on
the alkalinity, and is replaceable by other bases like MTBD or
Cs2CO3. Most importantly, the second but critical role of TBD is to
catalyze the reduction of peroxide intermediates, which
determines the selectivity. The formation of double hydrogen
bonds between peroxide and TBD results in an enhanced activity
of peroxide, allowing its reduction by DMSO toward the
hydroxylated product. As a support, the catalytic role of TBD on
the reduction of CHP and TBHP by d6-DMSO was confirmed.
Accordingly, the dual catalytic role of TBD enabled a green
strategy for aerobic oxygenation of C-H bonds, avoiding the
usage of either metal catalyst or hazardous stoichiometric
phosphine reductant. Considering the remarkable effect of TBD
to enhance the oxidizing ability of peroxides, we anticipate this
work to be a starting point in applications of TBD into oxidation
reactions where the peroxide plays the role as oxidant or
intermediate.
Acknowledgements
The authors gratefully thank Prof. Dr. Shengming Ma for helpful
discussions, and gratefully thank Mrs. Ling He for the nuclear
Overhauser effect spectroscopy (NOESY). This work was
supported by the Fundamental Research Funds for the Central
Universities, and the National Natural Science Foundation of
China (No. 22073081).
Figure 8. Proposed catalytic cycle for TBD-promoted hydroxylation of ketones.
Keywords: double hydrogen bonds • aerobic hydroxylation •
guanidine • peroxide • reaction mechanism
Consequently, reactivity of ketones should be affected by the
endothermic transformation from ketones to enols, because this
thermodynamic penalty will be added to each kinetic barrier
afterwards. In order to explain the reason for unreactive 1m and
1n, we calculated the Gibbs free energy change for enolization
(G1) of ketones (Table S2). G1 values for 1n (6.0 kcal/mol) and
1m (18.0 kcal/mol) were significantly higher than that of 1a (3.9
kcal/mol), causing reasonable inactivity of 1n and 1m. The
acylation of 1m at -carbon resulted in a sharp decreased G1
from 18.0 to -10.2 kcal/mol, which was in agree with the high
reactivity of 1j. Moreover, the methylation and phenylation of 1n
reduce G1 to 4.9 and 3.0 kcal/mol, leading to more and more
reactivity. The low selectivity for 1e could be explained by the
reactivity of its peroxide intermediate to form dioxetane, which
turned to byproduct after C-C cleavage.[6] We calculated the
Gibbs free energy change from peroxide intermediate to
dioxetane (G2, Table S2), and found G2 of 1e (8.7 kcal/mol) was
much lower than the values for 1a (13.1 kcal/mol), 1o (13.0
kcal/mol) and 1j (12.9 kcal/mol). Accordingly, easier formation of
dioxetane made the peroxide intermediate for 1e generate more
carboxylic acid, and less 2e.
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8
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RESEARCH ARTICLE
Entry for the Table of Contents
The dual catalytic role of TBD was revealed for the aerobic -hydroxylation of ketones under a metal- and phosphine-free method.
Via the doubly proton transfer process, TBD effectively activated the -C(sp3)-H bond of ketones, avoiding the necessity of alkali
metal. Most importantly, TBD enhanced the activity of peroxide intermediate through the double hydrogen bonds, allowing its
reduction by DMSO in absence of phosphine reductants.
9
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